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The Y1 Receptor for NPY: a Novel Regulator of Immune Cell Function

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The Y1 Receptor for NPY: a Novel Regulator of Immune Cell Function The Y1 receptor for NPY: a novel regulator of immune cell function Julie Elizabeth Wheway A submission to the University of New South Wales in candidature for the degree of Doctor of Philosophy Immunology and Inflammation Research Program Garvan Institute of Medical Research Darlinghurst, Sydney, Australia September 2006 i For Mum ii ABSTRACT Psychological conditions, including stress, compromise immune defenses. Although this concept is not novel, the molecular mechanism behind it remains unclear. Neuropeptide Y (NPY), regulates anxiety and is a part of the stress response. The NPY system also modulates immune functions such as cytokine release, cell migration, and innate immune cell activity. Postganglionic sympathetic nerves innervating lymphoid organs release NPY, which together with other peptides activate five receptors (Y1, Y2, Y4, Y5, and y6). Additionally, immune cells themselves release NPY following activation. Previous studies have shown that Y1 mediates NPY-immune effects and data presented here shows expression of Y1 on a wide range of immune cells. Results presented in this thesis, using Y1-deficient mice (Y1-/-), have uncovered a novel role for Y1 on immune cells. NPY acts endogenously to inhibit T cell activation whereas Y1-/- T cells are hyper-responsive to activation and trigger severe colitis after transfer into lymphopenic mice. Thus, signalling through the Y1 receptor on T cells inhibits T cell activation and controls the magnitude of T cell responses. Paradoxically, in Y1-/- mice, T cell differentiation to Th1 T cells appears to be defective as these mice were resistant to T helper type 1 (Th1) cell–mediated inflammatory responses and showed reduced levels of the Th1 cell–promoting cytokine interleukin 12 and reduced interferon γ production. This defect was due to functionally impaired antigen presenting cells (APCs). Y1-deficient APCs are defective in their ability to produce Th1-promoting cytokines and present antigens to T cells and consequently, Y1-/- mice had reduced numbers of effector T cells. Key reciprocal bone marrow chimera experiments indicated that this effect is intrinsic to immune cells and not driven by other Y1-expressing cell types. These results demonstrate a fundamental bimodal role for the Y1 receptor in the immune system, serving as a strong negative regulator on T cells as well as a key activator of APC function. The findings presented in this thesis uncover a sophisticated molecular mechanism regulating immune cell functions and thus adds to a growing number of signalling pathways shared by the immune and nervous system. iii PUBLICATIONS AND PRESENTATIONS ARISING FROM THIS THESIS MANUSCRIPTS Refereed Journals 1. Wheway J, Mackay C, Newton R, Sainsbury-Salis A, Boey D, Herzog H, Mackay F, A fundamental bimodal role for neuropetide Y1 receptor in the immune system J Exp Med. Dec 5;202(11):1527-38, 2005 Reviews Wheway J, Herzog H, Mackay F, The Y1 receptor for NPY: a key modulator of the adaptive immune system. Peptides, invited review, in press PRESENTATIONS Conference Presentations 1. Julie Wheway, Herbert Herzog, Fabienne Mackay, A fundamental bimodal role for neuropetide Y1 receptor in the immune system 15th Annual St Vincent’s & Mater Health Sydney Research Symposium- Sydney, October, 2005 2. Julie Wheway, Herbert Herzog, Fabienne Mackay, A Novel role for Neuropeptide Y1 receptor in regulating Th1 responses 34th Annual Scientific meeting of the Australasian Society for Immunology, Adelaide, December, 2004 3. Julie Wheway, Herbert Herzog, Fabienne Mackay, An Important role for NPY and receptors in regulating adaptive immune responses, 7th International Congress of Neuroimmunology, Venice, September, 2004 4. Julie Wheway, Herbert Herzog, Fabienne Mackay, An Important role for NPY and receptors in the immune system with therapeutic potential, 9th Australian Autoimmunity workshop, Sydney, May 2004 iv Invited Speaker Presentations 1. Julie Wheway, The Y1 receptor for NPY: a novel regulator of immune cell function. Hunter Institute of Medical Research/University of Newcastle Invited Speaker seminar series. Symposium- Newcastle, November, 2005 POSTERS 1. Julie Wheway, Dana Boey, Herbert Herzog, Fabienne Mackay, Role of NPY and PYY in immune responses: insights from knockout mice models. 8TH NPY Meeting, Florida, USA, April, 2006. 2. Julie Wheway, Rebecca Newton, Herbert Herzog, Fabienne Mackay, A Fundamental Bimodal Role Neuropeptide Y1 Receptor in Inflammatory Responses, 7th World Congress on Inflammation – Melbourne, August, 2005 3. Julie Wheway, Herbert Herzog, Fabienne Mackay, Important role for NPY in B cell homeostasis and migration, St Vincents Research Symposium, Sydney, September, 2003 4. Julie Wheway, Herbert Herzog, Fabienne Mackay, An important role for Neuropeptide Y in B Cell Function and Homeostasis, 33rd Annual Scientific Meeting of the Australasian Society of Immunology, Perth, December, 2003 v ACKNOWLEDGEMENTS The past three years have been an incredible journey and I have learnt a lot. There are many people who have helped me along the way: from those who genotyped to those who knew just the right moment to buy brownies. Firstly I would like to thank my supervisor Fabienne Mackay for her enthusiasm and support over the past 3 years. Her depth of knowledge I both admire and appreciate, and in having this opportunity to work with her, I have learnt a great deal. Thanks must also go to my co-supervisor, Rebecca Newton, to whom I’m very grateful for her input into the project during the first two years of my PhD. What began as a collaborative side project with the NPY group, has progressed into an unexpected and evolving area of research that I am proud to be a part of. I would sincerely like to thank Herbert Herzog for his foresight, contribution and interest in working with me on this project. I am optimistic about the future of this work and look forward to continuing to work with you in exploring this exciting area. Also thank you to my window into all things NPY: particularly Dana, Nikki and Amanda from Level 7, who welcomed me so readily. I have been very fortunate to be able to go to work every day with a supremely dynamic group of people on Level 10 at the Garvan Institute. I would especially like to mention the Lab 1 girls past and present; in particular Marcel, Kate, Jo, Carrie and Alexis. I cherish your friendship and ongoing support, valued indescribably during the difficult past 6 months. Thanks must also go to Sue and Melissa for their never-fuss attitude and formatting prowess. Equally worthy of mention are the Lab 1 coffee crew who graciously accepted my tea drinking ways. vi Does the universe allow a PhD student to simply sashay their way to completion without technical glitches? Through my world record total of four hard drive crashes, Ryan Evio and the Garvan IT department provided nothing but stellar assistance. This effort deserves more than a big thanks. To my family, I feel very fortunate to be related to such an amazing bunch of people and not a day goes without me being grateful for this. Dan, thank you for your patience, understanding and the ever-ready glass of wine at the end of the day. I am certainly looking forward to sharing the next part of this adventure with you. To the (hopefully soon to be fellow) Dr Wheway crew: Dad and Virginia. Thank you for challenging and stimulating me mentally and for helping me see life on the other side of a PhD. To Alison, Dalton and Ruby for always finding something much ‘better’ for me to do than writing my thesis. Through this you make me appreciate the real things in life. Finally to my mum, your strength and dignity is an inspiration to everyone who crosses your path. You have always been there for me but the importance of you being here to see me finish this cannot be taken lightly. I thank you and dedicate this PhD to you. vii TABLE OF CONTENTS ABSTRACT ........................................................................................................................................i Publications and presentations arising from this thesis .....................................................................iv Acknowledgements ...........................................................................................................................vi Table of contents .............................................................................................................................viii List of figures....................................................................................................................................xii List of tables ....................................................................................................................................xiv Abbreviations....................................................................................................................................xv 1 INTRODUCTION ......................................................................................................1 1.1 The mammalian immune system ................................................................................. 1 1.2 The innate immune response........................................................................................ 1 1.2.1 The TLR family .....................................................................................................................2 1.2.2 Cells of the innate immune response .....................................................................................2 1.3 The adaptive immune response...................................................................................
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